Cyclopentane derivatives

ABSTRACT

The disclosure relates to novel pentanor prostaglandin analogues, for example 15-(5-chloroindan-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid and 15-(5-chloroindan-2-yl)-11α,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid and the 1-ester and 1-alcohol derivatives thereof, to a process for their manufacture, to compositions containing them, and to their use in a method of inducing luteolysis.

This invention relates to new cyclopentane derivatives, and inparticular it relates to new cyclopentane derivatives which areanalogues of the naturally occurring compounds known as prostaglandin F₂α and prostaglandin E₂, showing a similar spectrum of pharmacologicalproperties and being useful for similar purposes. The relative potencyof the new compounds, however, in respect of the particularpharmacological effects shown is different from that of the abovenaturally occurring prostaglandins, and in particular they are morepotent as luteolytic agents than the corresponding naturalprostaglandins. That is to say, in general the prostaglandin F₂ αanalogues of the present invention are more potent than naturalprostaglandin F₂ α, and the prostaglandin E₂ analogues of the presentinvention are more potent than natural prostaglandin E₂. The newcompounds are, however, less potent as stimulants of uterine smoothmuscle than the corresponding natural prostaglandins F₂ α and E₂, andare therefore more selective in respect of luteolytic activity than thenatural prostaglandins. The new compounds are therefore advantageouswhen used as contraceptives, for the termination of pregnancy or forcontrol of the oestrus cycle, and are also useful as hypotensives or forthe relief of bronchospasm, and as inhibitors of blood plateletaggregation or of gastric secretion. The new compounds of the inventionare also useful for addition to semen intended for artificialinsemination of domestic animals, the success rate of insemination beingthereby increased, especially in pigs and cattle.

According to the invention there is provided a cyclopentane derivativeof the formula: ##SPC1##

Wherein R¹ is a carboxy or hydroxymethyl radical, or an alkoxycarbonylradical of up to 11 carbon atoms; either R² is a hydroxy radical or analkanoyloxy radical of 1 to 4 carbon atoms, and R³ is a hydrogen atom,or R² and R³ together form an oxo radical; X is an ethylene orcis-vinylene radical; Y is an ethylene or trans-vinylene radical Z is adirect bond or an alkylidene radical of 1 to 5 carbon atoms; either A isan alkylidene radical of 1 to 5 carbon atoms or an ethylene radical, andB is a direct bond, an oxygen or sulphur atom, or an alkylidene radicalof 1 to 5 carbon atoms, or A is an oxygen atom and B is an oxygen atom,an alkylideneoxy radical of 1 to 5 carbon atoms wherein the oxygen atomis linked directly to the benzene ring, or an alkylidene(alkylimino)radical [alkylidene-N(alkyl)-] wherein the alkylidene radical is of 1 to5 carbon atoms and the alkyl radical is of 1 to 4 carbon atoms, andwherein the nitrogen atom is linked directly to the benzene ring; R⁴ isa hydrogen atom or an alkyl radical of 1 to 4 carbon atoms, or CR⁴together with an adjacent carbon atom of A or B forms a double bond; R⁵is a halogen atom, or an alkyl, alkoxy or halogenoalkyl radical of 1 to3 carbon atoms, and n is 0, 1 or 2; which compound bears 0 or 1 alkylsubstituent of 1 to 4 carbon atoms on the trimethylene [--(CH₂)₃ --]group; and for those compounds wherein R¹ is the carboxy radical, thepharmaceutically- or veterinarily-acceptable base addition saltsthereof.

A suitable value for R¹ when it is an alkoxycarbonyl radical of up to 11carbon atoms is, for example, a methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyloctyloxycarbonyl, or decyloxycarbonyl radical, preferably straight chainsuch radicals.

A suitable value for R² when it is an alkanoyloxy radical of 1 to 4carbon atoms is, for example, an acetoxy or propionyloxy radical.

A suitable value for A or B when it is an alkylidene radical of 1 to 5carbon atoms is, for example, a methylene, ethylidene, propylidene orbutylidene radical. A suitable valve for B when it is an alkylideneoxyradical of 1 to 5 carbon atoms is, for example a methyleneoxy,ethylideneoxy or propylideneoxy radical, and a suitable value for B whenit is an alkylidene(alkylimino) radical is for example amethylene(methylimino), [--CH₂ N(CH₃)--]radical.

A suitable value for Z when it is an alkylidene radical of 1 to 5 carbonatoms is, for example, a methylene, ethylidene or propylidene radical.

A suitable value for R⁴ when it is an alkyl radical of 1 to 4 carbonatoms is, for example, a methyl or ethyl radical.

A suitable value for R⁵ when it is a halogen atom is, for example, thechorine, bromine, iodine or fluorine atom. A suitable value for R⁵ whenit is an alkyl or alkoxy radical of 1 to 3 carbon atoms is, for example,a methyl, ethyl, methoxy or ethoxy radical, and a suitable value when itis a halogenoalkyl radical of 1 to 3 carbon atoms is, for example, atrihalogenomethyl radical, for example the trifluoromethyl radical.

A suitable value for the alkyl substituent on the trimethylene group is,for example a methyl or ethyl radical. Possible values for the radical:##SPC2##

are therefore, the 1-benzocyclobutanyl, 1-benzocyclobutenyl, 1-indanyl,2-indanyl, 2-indanylmethyl, 2-(2-indanyl)ethyl,1,2,3,4-tetrahydro-2-naphthyl, 2-chromanyl, 2-indenyl,benzo[1,3]dioxol-2-yl, 2-benzo[ b]furyl, 2,3-dihydrobenzo[b]-fur-2-yl,2- and 3-benzo[b]thienyl, 2,3-dihydrobenzo[b]thien-2-yl,benzo[1,4]dioxan-2-yl and benzomorpholin-2-yl radicals, optionallysubstituted as defined above.

Particular values for the radical: ##SPC3##

wherein n is 1 or 2 are 5-chloroindan-2-yl, 5,6-dichloroindan-2-yl,5-methylindan-2-yl, 5-chlorobenzo[b]fur-2-yl,5-chloro-2-methylbenzo[b]fur-2-yl, 5-methoxybenzo[b]fur-2-yl and6-methoxybenzo[b]fur-2-yl radicals.

A suitable pharmaceutically- or veterinarily-acceptable base additionsalt is, for example the ammonium, alkyl-ammonium containing 1 to 4alkyl radicals each of 1 to 6 carbon atoms, alkanolammonium containing 1to 3 2-hydroxyethyl radicals, or alkali metal salt, for example thetriethylammonium, ethanolammonium, diethanolammonium, sodium, potassiumor ammonium salt.

It will be observed that the compounds of the formula I contain at leastfive asymmetric carbon atoms, namely carbon atoms 8, 9, 11, 12 and 15,the configurations at four of which, 8, 9, 11 and 12 are specified informula I, and that carbon atoms 2,3,4 and 16 may also be asymmetricallysubstituted, so that it is clear that such compounds can exist in atleast two optically active forms. It is to be understood that the usefulproperties of the racemate may be present to differing extents in theoptical isomers, and that this invention relates to the racemic form ofthe compounds of formula I and any optically active form which shows theabove useful properties, it being a matter of common knowledge how theoptically active forms may be obtained, and to determine theirrespective biological properties.

It is also to be understood that the above definition encompasses bothC-15 epimers, and that the terms "more polar" and "less polar" epimers,as applied hereinafter to compounds wherein C-16 is asymmetric, eachrelate to a pair of diastereoisomers.

A preferred group of cyclopentane derivatives of the invention comprisescompounds of the formula: ##SPC4##

wherein R¹ is a carboxy, methoxycarbonyl or hydroxymethyl radical, R² isa hydroxy radical and R³ is a hydrogen atom or R² and R³ together forman oxo radical, R⁴ is a hydrogen atom or a methyl radical, especially ahydrogen atom, A is an oxygen atom or a methylene radical, B is amethylene radical, and R⁵ is a hydrogen, chlorine or bromine atom,especially hydrogen or chlorine, or a methyl radical, and for thosecompounds wherein R¹ is a carboxy radical, the pharmaceutically- orveterinarily-acceptable base addition salts thereof as defined above.

Particular preferred compounds of the invention are15-(5-chloroindan-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid, methyl15-(5-cloroindan-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate,15-(5-chloroindan-2-yl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadien-1,9α,11α,15-tetraol,15-(5-chloro-2,3-dihydrobenzo[b]fur-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid, 9α,11α-15-trihydroxy-15-(2-methylindan-2-yl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid, 9α,11α,15-trihydroxy-15-(5-methylindan-2-yl)-16,17,18,19,20,-pentanor-5-cis,13-trans-prostadienoic acid,9α,11α,15-trihydroxy-15-(2-indanyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid and15-(5-chloro-2,3-dihydro-benzo[b]-fur-2-yl)-11α,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid.

The cyclopentane derivative of the invention may be manufactured bymethods known in themselves for the manufacture of chemically analogouscompounds. Thus, the following processes for the manufacture of thecyclopentane derivative of the formula I are provided as furtherfeatures of the invention:

a. for those compounds wherein R¹ is a carboxy radical, the hydrolysisof a compound of the formula: ##SPC5##

or of a mixed anhydride thereof, wherein A,B,R²,R³,R⁴,R⁵,n,X,Y and Zhave the meanings defined above, and R⁶ is a tetrahydropyran-2-yloxyradical or an acyloxy radical of 1 to 6 carbon atoms, and bearing 0 or 1alkyl substituent of 1 to 4 carbon atoms on the trimethylene group,whereafter if a salt is required the product so obtained is reacted witha base; or

b. for those compounds wherein R¹ is an alkoxycarbonyl radical of up to11 carbon atoms, the reaction of an acid of the formula I wherein R¹ isa carboxy radical, with a diazoalkane of up to 10 carbon atoms, or of asalt thereof, for example the sodium or silver salt with an alkyl halideof up to 10 carbon atoms, for example the alkyl iodide; or

c. for those compounds wherein R¹ is an alkoxycarbonyl radical of up to11 carbon atoms, the reaction of an acid of the formula IV, whereinA,B,R²,R³,R⁴,R⁵,n,X,Y and Z have the meanings stated above and R⁶ is atetrahydropyran-2-yloxy radical and bearing 0 or 1 alkyl substituent of1 to 4 carbon atoms on the trimethylene group, with an alkanol of 1 to10 carbon atoms in the presence of a strong acid, for exampletoluene-p-sulphonic acid, whereafter if the corresponding carboxylicacid is required, the ester so obtained is hydrolysed, for example withpotassium hydroxide; or

d. for those compounds wherein R¹ is a hydroxymethyl radical, thereduction of an ester of the formula I wherein R¹ is an alkoxycarbonylradical, for example an alkoxycarbonyl radical of up to 11 carbon atoms,with a complex metal hydride, for example lithium aluminium hydride; or

e. for those compounds wherein R¹ is a carboxy radical, R² is a hydroxyradical and R³ is a hydrogen atom, the reaction of a lactol of theformula: ##SPC6##

wherein A, B, R⁴, R⁵,n, Y and Z have the meanings defined above, with a(4-carboxybutyl)triphenylphosphonium salt, for example the bromide,bearing 0 or 1 alkyl substituent of 1 to 4 carbon atoms on thetrimethylene group, in the presence of a strong base, whereafter if asalt is required the product so obtained is reacted with a base; or

f. the reduction of a compound of the formula: ##SPC7##

wherein R¹,R³, R⁴, R⁵, A, B, X, Z and n have the meanings stated aboveand R⁷ and R⁸ are each a hydroxy or protected hydroxy radical, and whichbears 0 or 1 alkyl substituent of 1 to 4 carbon atoms on thetrimethylene group, for example with zinc borohydride, aluminiumtri-isopropoxide or di-isobornyloxy aluminium isopropoxide, whereafterwhen R⁷ and R⁸ are each a protected hydroxy radical the protectinggroups are removed and if a salt is required, a product so obtainedwherein R¹ is a carboxy group is reacted with a base; or

g. for those compounds wherein R² is a hydroxy radical and R³ is ahydrogen atom, the reduction, for example with a complex metal hydride,for example a lithium tri(lower alkyl)aluminium hydride such as lithiumtri-s-butyl aluminium hydride, or a borohydride, for example sodiumborohydride, of the corresponding compound wherein R² and R³ togetherform an oxo radical.

A suitable mixed anhydride is a mixed anhydride with a lower alkanoicacid, for example a lower alkanoic acid of up to 8 carbon atoms, forexample acetic acid, and a suitable phosphonium salt is, for example,the bromide.

The hydrolysis in process (a) may be carried out under either acidic orbasic conditions, for example in aqueous acetic acid, when R⁶ is atetrahydropyranyl radical, or in an aqueous or alcoholic solution of analkali metal carbonate, for example potassium carbonate in methanol,when R⁶ is an acyloxy radical, and it may be carried out at ambienttemperature or at an elevated temperature of up to 60°C.

The starting material of the formula IV, wherein X is a cis-vinyleneradical and Y is a trans-vinylene radical, R² is a hydroxy radical andR³ is a hydrogen atom, may be obtained by reaction of the known aldehydeVII (Ac = acetyl or p-phenylbenzoyl) with a phosphonate of the formula(CH₃ O)₂ PO.CH₂ CO.ZR⁹ wherein R⁹ is ##SPC8##

(which is prepared from dimethyl methylphosphonate and an esterR⁹.Z.COOAlkyl) in the presence of a strong base, or with a phosphoraneof the formula R⁹ Z.CO.CH:PPh₃ (which is prepared, for example, fromtriphenylphosphine and a compound of the formula R⁹.Z.CO.CH₂ I), to givean enone VIII. The enone VIII is reduced with zinc borohydride or analuminium trialkoxide, for example aluminium tri-isopropoxide, to thecorresponding enol IX, and the protecting acyl group is then removedwith potassium carbonate in methanol to give a diol X. ##SPC9##

Ac represents an acetyl or p-phenylbenzoyl radical. The diol X is eitherreduced with di-isobutyl aluminium hydride to the lactol startingmaterial of the formula IV, or is protected as a bis-tetrahydropyranylether X and the lactone ring is then reduced with di-isobutyl aluminiumhydride to give a lactol XII (R⁶ = tetrahydropyran-2-yloxy).Alternatively, the diol X is reduced directly with di-isobutyl aluminiumhydride to give a triol which may be acylated and selectively hydrolysedto give the lactol bis-ester (XII, R⁶ = acyloxy). A lactol XII isreacted with the phosphonium ylide anion obtained from (4-carboxybutyl)triphenyl-phosphonium bromide and a strong base, to give a carboxylicacid of the formula IV.

The starting material of the formula IV wherein X is an ethyleneradical, used in the process of the invention, may be obtained byselective hydrogenation of the corresponding compound of the formula IVwherein X is the cis-vinylene radical, and the starting material of theformula IV wherein Y is the ethylene radical may be obtained byhydrogenation of an intermediate X or XI, and using the hydrogenationproduct in place of the intermediate X or XI in the remainder of theabove-described reaction sequence.

The starting material of the formula IV wherein R² is an alkanoyloxyradical may be obtained from the corresponding compound wherein R² is ahydroxy radical by acylation with an acid anhydride in pyridine to givea 9-ester-1-mixed anhydride.

The starting material of the formula IV wherein R² and R³ together formthe oxo radical, may be obtained from the corresponding startingmaterial of the formula IV wherein R.sup. 2 is hydroxy and R.sup. 3 ishydrogen, by oxidation with Jones' reagent (chromic acid in acetone),followed, as required, by hydrolysis of the tetrahydropyranyl protectinggroups or esterification of the carboxylic acid group.

The starting material of the formula V may be obtained by acidhydrolysis of the corresponding bis(tetrahydropyranyl ether) XII, (R⁶ =tetrahydropyran-2-yloxy).

A starting material of the formula VI may be obtained from the knowncompound 4β-dimethoxymethyl-2,3,3aβ,6aβ-tetrahydro-5α-hydroxy-6β-iodo-2-oxocyclopenteno [b]furan (XIII) by treatment withtributyl tin hydride to give the de-iodinated lactone XIV. The5α-hydroxy group is protected as the tetrahydropyran-2-yl ether XV, thelactone is reduced to the lactol XVI, using di-isobutyl aluminiumhydride, and the lactol is reacted with(4-carboxy-butyl)-triphenylphosphonium bromide to give the cyclopentanolderivative XVII, which by reaction with toluene-p-sulphonic acid inmethanol gives a methyl ester XVIII. The hydroxy groups are esterified,for example with 4-phenylbenzoyl chloride to give XIX, and the acetal ishydrolysed to an aldehyde XX which is reacted with a phosphonate (CH₃O)₂ PO.CH₂ CO.ZR⁹ or a phosphorane Ph₃ P:CH.CO.ZR⁹ in the presence of astrong base, to give the required starting material of the formula VI,wherein X is cis-vinylene, and R⁷ and R⁸ are each an alkanoyloxy oraroyloxy radical.

If a starting material of the formula VI wherein X is an ethyleneradical is required, the methyl ester XVIII is hydrogenated, and thehydrogenated methyl ester is ##SPC10##

Pb = 4-phenylbenzoyl, THP = tetrahydropyran-2-yl.

used instead of the methyl ester XVIII in the following steps of theprocess.

Alternatively, the cyclopentanol derivatives XVII is esterified withdiazomethane to a methyl ester XXI, and the hydroxy radical is alsoesterified, for example with 4-phenylbenzoyl chloride, to give XXII. Thetetrahydropyranyl ether group is hydrolysed with dilute acid inmethanol, and the acetal XXIII is hydrolysed in a two phase system ofconcentrated hydrochloric acid in chloroform, to give a requiredstarting material VI, wherein X is a cis-vinylene radical, R⁷ is a4-phenylbenzoyloxy radical and R⁸ is a hydroxy radical.

It is, of course, to be understood that an optically active compound ofthe invention may be obtained either by resolving the correspondingracemate, or by carrying out the above-described reaction sequencesstarting from an optically active intermediate, for example from anoptically active aldehyde of the formula VI (Ac = acetyl orp-phenylbenzoyl).

As stated above, the compounds of the invention possess a profile ofpharmacological properties which differs from that of the naturallyoccuring prostaglandins F₂ α and E₂. Thus, for example,15-(5-chloro-2,3-dihydrobenzo[b]fur-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid and9α,11α,15-trihydroxy-15-(5-chloro-2-indanyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid are each approximately 50 times as ##SPC11##

active as prostaglandin F₂ α in a luteolytic test in the hamster (oraldosing), but have only about one fifth of the smooth muscle stimulantactivity of prostaglandin F₂ α. No indication of toxicity has been notedwith any compound of the invention at the dose levels used.

Also as stated above, the compounds of the invention are useful, forexample, for the induction of labour in childbirth, and for this purposeare used in the same way as it is known to use the naturally-occurringprostaglandins E₁ and E₂, that is to say, by administering a sterile,substantially aqueous solution containing from 0.01 to 10μg./ml.,preferably 0.01 to 1μg./ml. of active compound, the intravenous,extraovular or intra-amniotic administration until labour commences.Also, for this purpose, the compounds of the invention may be used incombination or concurrently, with a uterine stimulant, for exampleoxytocin, in the same way that it is know to use prostaglandin F₂ α incombination, or concurrently with oxytocin for the induction of labour.

When a compound of the invention is to be used for the control of theoestrus cycle in animals, it may be used in combination, orconcurrently, with a gonadotrophin, for example PMSG (pregnant mareserum gonadotrophin) or HCG (human chorionic gonadotrophin) to hastenthe onset of the next cycle.

Thus, according to a further feature of the invention there is provideda pharmaceutical or veterinary composition comprising a cyclopentanederivative of the invention, together with a pharmaceutically orveterinarily acceptable diluent or carrier.

The compositions may be in a form suitable for oral administration, forexample tablets or capsules, in a form suitable for inhalation, forexample an aerosol or a solution suitable for spraying, in a formsuitable for parenteral or infusion administration, for example sterileinjectable aqueous or oily solutions or suspensions, or in the form of asuppository, suitable for anal or vaginal use.

The compositions of the invention may be prepared by conventional means,and may incorporate conventional excipients, and a preferred compositionis a sterile, substantially aqueous solution containing between 0.01 and10.0μg./ml. of a compound of the invention.

The invention is illustrated, but not limited, by the followingExamples. R_(F) values refer to thin layer chromatography on silica gelplates supplied commercially by Merck of Darmstadt, and the spots weredetected either by fluorescence, or by spraying the plates with asolution of ceric ammonium nitrate in sulphuric acid. Mass spectrum datafor F-series compounds refer to the per(trimethylsilyl) derivatives,that is, normally, tetra-trimethylsilyl derivates of compounds whereinR¹ is carboxy or hydroxymethyl, and tris-trimethylsilyl derivatives ofcompounds wherein R¹ is an alkoxycarbonyl radical. Mass spectrum datafor E-series compounds refer normally to thetris-trimethylsilyl-9-methoxime derivatives.

Example 1

A solution of9α-hydroxy-15-(2,3-dihydrobenzo[b]fur-2-yl)-11α,15-bis-(tetra-hydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid (193mg.) in 3ml. of a 2:1 mixture of acetic acid and water, wasstirred at 50°C. for 2 hours. The solvents were evaporated, the residuewas dissolved in dilute aqueous sodium bicarbonate solution (2ml.) andthe solution was extracted with ethyl acetate (3 × 2ml.) and theextracts were discarded. The aqueous solution was acidified to pH 4 with2N aqueous oxalic acid and the acidified solution was extracted withethyl acetate (4 × 5ml.). The ethyl acetate extracts were washed with a1:1 mixture of saturated brine and water, and were then dried. Afterevaporation of the ethyl acetate, the residue consisted of a mixture ofthe C-15 epimers of9α,11α,15-trihydroxy-15-(2,3-dihydrobenzo[b]fur-2-yl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid. Thin-laverchromatography on silica gel plates, supplied commercially by Merck ofDarmstadt, using a mixture of 3% acetic acid in ethyl acetate as thedeveloping solvent, separated the C-15 epimers, having R_(F) values of0.3 and 0.4, respectively. The n.m.r. spectrum of each isomer (indeuterated acetone) showed the following characteristic bands (δvalues):

3.12, 2H, doublet, benzofuryl C-3 protons,

3.7-5.0, 7H, multiplet, 3-CH(OH)-and benzofuryl C-2 protons,

5.2-5.8, 4H, multiplet, olefinic protons,

6.6-7.2, 4H, multiplet, aromatic protons.

The mass spectrum of the more polar epimer had M⁺ = 675.3365 (calculatedfor C₃₅ H₆₂ O₆ Si₄ = 675.3391).

The bis-tetrahydropyranyl ether used as starting material may beprepared as follows:

n-Butyl-lithium (33ml. of a 2.1M solution in hexane) was added to asolution of dimethyl methylphosphonate (8.5g.) in dry tetrahydrofuran at-78°C. in an atmosphere of nitrogen. After 10 minutes, a solution ofmethyl 2,3-dihydrobenzo[b]furan-2-carboxylate (6.09g.) in drytetrahydrofuran (35ml.) was added dropwise, and the mixture was stirredfor 4 hours at -78°C. The reaction mixture was neutralised with aceticacid and the solvents were removed under reduced pressure. The residuewas shaken with a mixture of ether (100ml.) and water (20ml.), and theorganic phase was separated and washed with brine. The solution wasdried, the solvents were evaporated and the residue was used withoutpurification. R_(F) = 0.5 (10% methanol in ethyl acetate).

A solution of dimethyl 2-oxo-2-(2,3-dihydrobenzo[b]-fur-2-yl)ethylphosphonate (1.05g.) in dry 1,2-dimethoxyethane (20ml.) at -78°C. wastreated with n-butyl-lithium (1.57ml. of a 2.1M solution in hexane), andthe mixture was stirred for 15 minutes. To this mixture was added asolution of 5α-(4-phenylbenzoyloxy)-4β-formyl-2-oxo-2,3,3aβ , 6aβ-tetrahydrocyclopenteno[b]furan (1.05g.) in 1,2-dimethoxyethane (20ml.),and after 1 hour the reaction mixture was neutralised with glacialacetic acid and all solvents were removed by evaporation under reducedpressure below 35°C. The residue was triturated with ether to yield theunsaturated ketone product as a white solid, R_(F) = 0.7 (1:1 ethylacetate/toluene). The n.m.r. spectrum in deuteriochloroform showed thefollowing characteristic features (δ values):

5.0-5.4, 3H, multiplet, C-5,C-6a and benzofuryl C-2 protons,

6.5-7.3, 6H, multiplet, olefinic and benzofuryl aromatic protons,

7.4-8.2, 9H, multiplet, other aromatic protons.

To a solution of the unsaturated ketone (566mg.) in toluene (25ml.) wasadded a solution of diisobornyloxyaluminium isopropoxide (8.9ml. of a6.32M solution in toluene). After 10 minutes at room temperaturesaturated sodium hydrogen tartrate solution was added and the mixturewas stirred for 10 minutes. Ethyl acetate (50ml.) was added, the organicphase was separated and dried, and the solvent was evaporated underreduced pressure to yield a mixture of epimeric enols R_(F) = 0.4 and0.5 (25% methylenedichloride in ethyl acetate), contaminated withiso-borneol.

To a solution of the crude enol mixture (563mg.) in a mixture ofmethanol and methylene dichloride (4:1) was added anhydrous potassiumcarbonate (175mg.). After stirring for 3 hours at room temperature, themixture was acidified to pH 5 with hydrochloric acid, and diluted withethyl acetate (50ml.). This mixture was washed successively withsaturated sodium bicarbonate solution and brine. The organic phase wasseparated and dried, and the solvents evaporated under reduced pressure.The crude product was chromatographed on "Florisil" (trademark) usingether as eluent, to yield an epimeric mixture of diols, R_(F) = 0.3 (5%methanol in methylene dichloride). The n.m.r. spectrum indeuteriochloroform showed the following features (δ values):

3.7-5.0, 4H, multiplet, C-5, C-6a, C-15 and benzofuryl C-2 protons,

5.63, 2H, multiplet, olefinic protons,

6.6-7.3, 4H, multiplet, aromatic protons.

To a solution of the epimeric diols (244mg.) in methylene chloride(2.5ml.) under an atmosphere of nitrogen were added successivelyredistilled 2,3-dihydropyran (0.7ml.) and a solution of anhydroustoluene-p-sulphonic acid in tetrahydrofuran (0.1ml. of a 1% solution).

After 10 minutes, pyridine (3 drops) was added, followed by ethylacetate (40ml.). The solution was washed successively with saturatedsodium bicarbonate solution and saturated brine, and was dried.Evaporation of the solvents gave a mixture of epimericbis-tetrahydropyranyl ethers as a clear oil, R_(F) = 0.6 (ethylacetate).

To a solution of the epimeric bis-tetrahydropyranyl ethers (390mg.) indry toluene (20ml.) under an atmosphere of nitrogen at -78°C. was added1.44ml. of a 2.2m mole/ml. solution of di-isobutylaluminium hydride intoluene. After 15 minutes the reaction was quenched by the dropwiseaddition of methanol (3ml.) and after a further 15 minutes at roomtemperature a mixture of 1:1 saturated brine/water (25ml.) was added,and the mixture was extracted with ethyl acetate (3 × 50ml.). Theextract was washed with saturated brine, and dried, and the solventswere evaporated to give a mixture of epimers of thebis-(tetrahydropyranyl ether) lactol,4β-[4-(2,3-dihydrobenzo[b]fur-2-yl)-3-(tetrahydropyran-2-yloxy)-1-trans-butenyl]-2,3,3aβ,6aβ-tetrahydro-2-hydroxy-5α-(tetrahydropyran-2-yloxy)cyclopenteno[b]furan,R_(F) = 0.5 (5% methanol in methylene dichloride).

Finely powdered (4-carboxybutyl)triphenylphosphonium bromide (886mg.)was heated to 100°C. under vacuum for 1 hour. The evacuated reactionvessel was filled with an atmosphere of dry nitrogen, the solid wasdissolved in dimethylsulphoxide (5ml.) and the solution was cooled toroom temperature. To this solution was added dropwise 1.93 ml. of a 2Msolution of methanesulphinylmethyl sodium in dimethylsulphoxide followedby a solution of the mixture of epimers of the bis-(tetrahydropyranylether) lactol (373 mg.) in a mixture of dimethylsulphoxide (10ml.) andbenzene (2ml.). The solution was stirred for 3 hours, and the solventwas removed by evaporation under reduced pressure at a temperature below40°C. The residue was shaken with water (10ml.) and ethyl acetate(10ml.) and the aqueous phase was separated, extracted with ethylacetate (2 × 10ml.) and the extracts discarded. The aqueous solution wasacidified to pH 3-4 with 2N aqueous oxalic acid, and extracted with amixture of equal parts of ether and petroleum ether (b.p. 40°-60°C.) (5× 10ml.). The organic phase was separated, washed with saturated brineand was dried. Evaporation of the solvents gave15-(2,3-dihydrobenzo[b]fur-2-yl)-9α-hydroxy-11α,15-bis-(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid as a clear oil, R_(F) = 0.3, (5% methanol inmethylene dichloride).

EXAMPLE 2

Methyl15-(benzo[1,4]dioxan-2-yl)-15-oxo-9α,11α-di-(4-phenylbenzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate(185mg.) was stirred in dry toluene (4.0ml.) under argon at roomtemperature, and treated with a 0.323M solution ofdi-isobornyloxyaluminium isopropoxide in toluene (2.17ml., 3equivalents). After 11/4 hours, the mixture was partitioned betweenwater (0.5ml.) and ethyl acetate (1.0ml.), and filtered through `Hvflo`(trademark) washing the filter pad with ethyl acetate (2 × 4ml.). Theorganic layer was separated, washed with brine (4ml.), dried overmagnesium sulphate and filtered, and the solvent was evaporated to leavea crude oily product, which was chromatographed on `Florisil` (2g.).Elution with 5-10% ethyl acetate in toluene gave the enol, methyl15-(benzo[1,4]dioxan-2-yl)-15-hydroxy-9α,11α-di-(4-phenylbenzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate,R_(F) = 0.4 (25% ethyl acetate in toluene).

The enol (64mg.) was stirred at room temperature under argon in amixture of methanol (0.8ml.), water (0.6ml.) and acetone (1.0ml.) withpotassium hydroxide (0.8ml. of a 1M solution in methanol), for 16 hours.The solvents were evaporated under reduced pressure and the residue waspartitioned between water (12ml.) and ether (3 × 10ml.). The aqueouslayer was separated and filtered through `Hvflo` washing the filter padwith water (2ml.). The filtrate was acidified to pH 1 with 2Nhydrochloric acid and extracted with ether (3 × 10ml.). The combinedether extracts were washed in brine (5ml.), dried over magnesiumsulphate and filtered, and the solvent was evaporated to leave a solidresidue consisting of 4-phenylbenzoic acid and a mixture of the C-15epimers of15-(benzo[1,4]dioxan-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid. The epimers were separated by preparative thin layerchromatography on silica gel, R_(F) = 0.3 and 0.4 (5% acetic acid inethyl acetate). The n.m.r. spectrum of each epimer in deuteriochloroformshowed the following characteristic features (δ values):

3.8-4.3, 6H, multiplet, 3>CH(OH) and C-2 and

C-3 protons of the benzodioxanyl radical,

4.8, 3H, broad, 3 hydroxy protons,

5.1-5.8, 4H, multiplet, olefinic protons,

6.88, 4H, singlet, aromatic protons.

The mass spectrum of the more polar epimer had M⁺ = 706.3562 (calculatedfor C₃₅ H₆₂ O₇ Si₄ = 706.3574).

The methyl15-(benzo[1,4]dioxan-2-yl)-15-oxo-9α,11α-di-(4-phenylbenzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoateused as starting material may be prepared as follows:

Methyl benzo[1,4]dioxan-2-carboxylate was converted to dimethyl[2-(benzo[1,4]dioxan-2-yl)-2-oxo]ethylphosphonate by the processdescribed in the second part of Example 1, b.p. 234°C. at 0.1mm./Hg,R_(F) = 0.3 (50% ethyl acetate in toluene).

A solution of dimethyl [2-(benzo[1,4]dioxan-2-yl)-2-oxo]ethylphosphonate(131mg.) (1.5 equivalent) in dimethoxyethane (2.0ml.) was stirred underargon and cooled in a chloroform/`Drikold` bath, and treated with 2.2Mbutyllithium in hexane (177μl.) followed after a few minutes by asolution of methyl7-[2β-formyl-3α,5α-di(4-phenylbenzoyloxy)-cyclopent-1.alpha.-yl]hept-5-cis-enoate(225.7mg.), also in dimethoxyethane (1.5ml.). The cooling bath was thenremoved, and after 2 hours a few drops of acetic acid and then water(200μl.) were added to adjust the pH to about 6. The solvent wasevaporated under reduced pressure and the residue was partitionedbetween water (15ml.) and ethyl acetate (1 × 30ml., 1 × 15). The organiclayer was separated, washed with water (10ml.) then dried over magnesiumsulphate, and filtered, and the solvent was evaporated to give a viscousoil. This oil was purified either by chromatography on `Florisil` (2g.)eluting with 5% ethyl acetate in toluene or by trituration with methanol(10ml.), to afford the enone, methyl15-(benzo[1,4]dioxan-2-yl)-15-oxo-9α,11α-di(4-phenyl-benzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate, R_(F) = 0.7 (ether).

The aldehyde, methyl7-[2β-formyl-3α,5α-di(4-phenylbenzoyloxy)cyclopent-1.alpha.-yl]hept-5-cis-enoate,used in the above process, may be prepared as follows:

4β-Dimethoxymethyl-2,3,3aβ,6aβ-tetrahydro-5α-hydroxy-6β-iodo-2-oxocyclopenteno[b]furan(4.0g.) in dry toluene (40ml.) was stirred under argon at 80°C. withtri-n-butyl tin hydride (6.6g.) for 18 hours. The solvent was evaporatedunder reduced pressure and the residue was stirred with petroleum ether(b.p. 40°-60°C., 100ml.) for 30 minutes. The solvent was decanted andthe residual oil was chromatographed on "Florisil" (trade mark) (50g.).Elution with mixtures containing 25% ethyl acetate in toluene andfinally with ethyl acetate gave4β-dimethoxymethyl-2,3,3aβ,6aβ-tetrahydro-5α-hydroxy-2-oxocyclopenteno[b]furanas an oil, R_(F) = 0.3 (20% acetone im chloroform). The n.m.r. spectrumin deuteriochloroform showed the following characteristic peaks (δvalues):

    3.40 and 3.42, 6H, 2 singlets, methoxy                                        4.04-4.36      1H, multiplet, 5β proton,                                                1H, doublet, -CH(OMe).sub.2,                                                  1H, multiplet, 6aβ proton.                            

4β-Dimethoxymethyl-2,3,3aβ,6aβ-tetrahydro-5α-hydroxy-2-oxocylcopenteno[b]furan(4.01g.) was stirred under argon in dry toluene (30ml.), and theresulting solution was treated with an excess of freshly distilled2,3-dihydropyran (17ml.), followed by 2.0ml. of a 0.1% w/v solution oftoluene-p-sulphonic acid in dry tetrahydrofuran. After three-fourthshour, the mixture was treated with pyridine (0.50ml.) and thenpartitioned between ethyl acetate (150ml.) and saturated sodiumbicarbonate (75ml.). The organic layer was separated, washed withsaturated brine (50ml.), dried over magnesium sulphate and filtered, andthe solvent was evaporated to give a crude lactone,4β-dimethoxymethyl-2,3,3aβ,6aβ-tetrahydro-2-oxo-5α-(tetrahydropyran-2-yloxy)-cyclopenteno[b]furan,R_(F) = 0.70 (20% acetone in chloroform). The crude lactone (6.2g.) wasdissolved by stirring in dry 1,2-dimethoxyethane (120ml.) under argon atabout -60°C. (chloroform - `Drikold` (trademark) cooling bath), and 1.7Mdi-isobutylaluminium hydride (11.2ml.) was added. After 30 minutes,methanol (3ml.) was added, the mixture was allowed to warm up to roomtemperature, and was partitioned between ethyl acetate (600ml.) and 1:1saturated brine/water (300ml.). The whole mixture was filtered throughkeiselguhr ("Hyflo" - trade mark) and the two phases were separated. Theaqueous phase was reextracted with ethyl acetate (300ml.) and thecombined organic layers were washed with water (100ml.), dried overmagnesium sulphate and filtered, and the solvents were evaporated togive the crude lactol,4β-dimethoxymethyl-2,3,3aβ,6aβ-tetrahydro-2-hydroxy-5.alpha.-(tetrahydropyran-2-yloxy)-cyclopenteno[b]furan,as an oil, R_(F) = 0.4 (20% acetone in chloroform).

A stirred solution of (4-carboxybutyl)triphenylphosphonium bromide(24.8g.) in dry dimethylsulphoxide (DMSO, 50ml.), was treated slowlyunder argon and with cooling in an ice-water bath, with 2Mmethanesulphinylmethyl sodium in DMSO (54.5ml., 2.5 equivalents) to forma solution of the corresponding ylide. The crude lactol (6.3g.) in dryDMSO (150ml.) was then added to the ylide solution at room temperature.The mixture was stirred for 11/4 hours, then water (1ml.) was added. TheDMSO was then evaporated at high vacuum at a temperature not exceeding50°C. The residual gum was partitioned between ether (4 × 225ml.) andwater (150ml.). The aqueous layer was separated, acidified with 2Noxalic acid to approximately pH 4, and then extracted with 1:1 mixtureof ether and pentane (3 × 300ml.). The extracts were washed withsaturated brine (150ml.), dried over magnesium sulphate and filtered,and the solvent was evaporated to give the crude acid,7-[2β-dimethoxymethyl-5α-hydroxy-3α-(tetrahydropyran-2-yloxy)cyclopent-1α-yl]hept-5-cis-enoicacid as an oil, suitable for use in the next stage of the synthesis. Asample was purified by chromatography on silica (70:1) eluting theproduct with 2% methanol in toluene as an oil, R_(F) = 0.4 (5% methanolin methylene chloride). The n.m.r. spectrum in deuteriochloroform showedthe following characteristic peaks (δ values):

    3.35, 6H, singlet, methoxy,                                                   3.3-3.65, 1H,                                                                 3.68-4.0, 1H,                                                                 4.00-4.19, 2H,     multiplets, >CH--O--                                       4.19-4.38, 1H,                                                                4.6-4.8, 1H,                                                                  5.09-5.78, 2H, multiplet, olefinic protons                                

The crude acid (4.48g.) in methanol (45ml.) was stirred under argon atroom temperature with toluene-p-sulphonic acid (240mg.) for 23/4 hours.The solution was then partitioned between ethyl acetate (300ml.) andsaturated sodium bicarbonate (60ml.) followed by saturated brine(60ml.). The organic phase was dried over magnesium sulphate andfiltered, and the solvent was evaporated to leave a crude ester-diol,methyl7-[2β-dimethoxymethyl-3α,5α-dihydroxycyclopent-1α-yl]hept-5-cis-enoateas an oil, P_(F) = 0.65 (10% methanol in methylene chloride). The n.m.r.spectrum in deuteriochloroform showed the following principal peaks (δvalues):

    3.39, 6H, singlet,                                                                             3 methyl groups,                                             3.64, 3H, singlet,                                                            4.03-4.3, 3H,  multiplet, >CH--O--                                                           doublet, >CH(OMe).sub.2                                        5.1-5.7, 2H, multiplet, olefinic protons.                                 

The crude ester-diol (3.3g) was dissolved in dry pyridine (50ml.) underargon, and treated with p-phenylbenzoyl chloride (9.2g.), and themixture was stirred for 17 hours. Water (0.8ml.) was then introduced andstirring was continued for 3-4 hours. The mixture was evaporated underreduced pressure and toluene was added to assist azeotropic removal ofthe pyridine. The residue was partitioned between toluene (300ml.) andsaturated sodium bicarbonate solution (150ml.). The whole mixture wasfiltered through `Hyflo` and the organic phase was separated. Theaqueous layer was extracted with toluene (150ml.), and the organicextracts were combined, washed with brine (100ml.), dried over magnesiumsulphate, and filtered, and the solvent was evaporated to leave a solidcrystalline residue. This was thoroughly triturated with methanol(70ml.), the mixture was filtered, and the product was washed with moremethanol (3 × 10ml.) to give the dimethyl acetal, methyl7-[2β-dimethoxymethyl-3α,5α-di-(4-phenylbenzoyloxy)cyclopent-1α-vl]hept-5-cis-enoate as a white solid, m.p. 104.5°-106.5°C., R_(F) = 0.5(5% acetone in toluene). The n.m.r. spectrum in deuteriochloroformshowed the following characteristic signals (δ values): ##EQU1##

An analytical sample recrystallised three times from ethanol had m.p.105°-107°C. The dimethyl acetal was vigorously stirred under argon for10 minutes in a two-phase system consisting of 2% isopropanol inchloroform (20ml.) and concentrated hydrochloric acid (10ml.). Thechloroform layer was separated and the aqueous layer was extracted withchloroform (20ml.). The organic layers were combined, washedsuccessively with aqueous saturated sodium bicarbonate (20ml.) andsaturated brine (10ml.), dried over magnesium sulphate and filtered, andthe solvent was evaporated. The oily residue crystallised on dryingunder high vacuum to give methyl7-[2β-formyl-3α,5α-di-(4-phenylbenzoyloxy)cyclopent-1.alpha.-yl]hept-5-cis-enoate,R_(F) = 0.4 (5% ethyl acetate in toluene). The n.m.r. spectrum indeuteriochloroform was consistent with the required structure, andshowed the following principal signals (δ values):

    3.51, 3H, singlet, methyl ester,                                              5.3-5.6, 4H, multiplet, >CH--O-- and olefinic protons,                        7.8-8.0, 2H,                                                                  doublets,                                                                     8.0-8.2, 2H,                                                                  7.22-7.73, 14H, multiplet, rest of aromatic protons,                          10.01-10.14, 1H, doublet, --CHO.                                          

An analytical sample, m.p. 93°-97°C., was obtained by triturating theabove-described product with ether.

Example 3

The process described in Example 1 was repeated using9α-hydroxy-15-(2-indanyl)-11α,15-bis-(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid in place of the corresponding benzofuryl compound, to give9α,11α,15-trihydroxy-15-(2-indanyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid, R_(F) = 0.4 and 0.5. (3% acetic acid in ethyl acetate). The n.m.r.spectrum of each epimer in deuteriochloroform showed the followingcharacteristic peaks (δ values):

2.85, 4H, doublet, indanyl C-1 and C-3 protons,

3.2-4.1, 8H, multiplet, 3>CH.0-, 4 exchangable

protons and indanyl C-2 proton,

7.0-7.2, 4H, multiplet, aromatic protons;

The mass spectrum of the more polar isomer had M⁺ = 688.3827,(calculated for C₃₆ H₆₄ O₅ Si₄ = 688.3832) prepared via the followingintermediates:

dimethyl [2-(2-indanyl)-2-oxo]ethylphosphonate b.p. 85°C. at 0.1 mm.Hg.;

unsaturated ketone, R_(F) = 0.6 (50% ethyl acetate in toluene). Massspectrum gave (M- 4-phenylbenzoic acid)⁺ = 294.1227, calculated for C₁₉H₁₈ O₃ = 294.1255;

enol R_(F) = 0.3 and 0.25 (50% ethyl acetate in toluene);

diol, R_(F) = 0.4 (ethyl acetate);

bis-(tetrahydropyranyl ether) R_(F) = 0.7 (ethyl acetate);

bis-(tetrahydropyranol ether) lactol, R_(F) = 0.6 (ethyl acetate);

9α-hydroxy-15-(2-indanyl)-11α,15-bis-(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, R_(F) = 0.4 (ethyl acetate)

Example 4

The process described in Example 1 was repeated, using the appropriatephosphonate reagent, to give the compounds shown below. The productswere identified by n.m.r. spectroscopy and are characterised below byaccurate mass measurement by mass spectrometry of the molecular ion ofthe tetra(trimethylsilyl)derivative. The phosphonate reagent and theunsaturated ketone intermediate of the formula VIII, (Ac =p-phenylbenzoyl) have been characterised, and appropriate data for thesecompounds are also given. ##SPC12##

    __________________________________________________________________________                           Mass spectrum Phosphonate  Enone of formula VIII       No.     R.sup.9  Isomer*                                                                             Found  Calculated                                                                           R.sub.F      Ac = p-phenylbenzoyl        __________________________________________________________________________    1   5-chloro-2,3-dihydro-                                                                      l.p.   724          0.38                                         benzo[b]fur-2-yl                                                                           m.p.  M.sup.+=      (ethyl acetate)                                                                            m.p. 161-163°C.                             724.3166                                                                             724.3235                                        2   2-benzo[1,3]dioxolyl                                                                       l.p.   692          0.29         R.sub.F = 0.6                                m.p.  M.sup.+=      (50% ethyl acetate                                                                         (50% ethyl acetate in                              692.3424                                                                             692.3417                                                                             methylene dichloride)                                                                      toluene)                    3   1-benzocyclobutyl                                                                          mixed M.sup.+=                                                                             674.3676                                                                             0.35         R.sub.F = 0.45                                     674.3686      (5% methanol in ethyl                                                                      (25% ethyl acetate in                                            acetate)     toluene)                    __________________________________________________________________________     *l.p. = less polar isomer                                                      m.p. = more polar isomer                                                

Example 5

The process described in Example 2 was repeated using the appropriatephosphonate reagent, to give the compounds shown below. The productswere identified by n.m.r. spectroscopy and are characterised below byaccurate mass measurement by mass spectrometry of the molecular ion orthe (M - methyl)⁺ ion, whichever is more appropriate, of the tetra(trimethylsily) derivative. The phosphonate reagent and the unsaturatedketone intermediate of the formula VI have been characterised andappropriate data for these compounds are also given. ##SPC13##

    __________________________________________________________________________                               Mass spectrum    Phosphonate                                                                             Enone                   No.     R.sup.9       Isomer*                                                                              Found   Calculated                                                                           R.sub.F                                                                              of the formula             __________________________________________________________________________                                                       VI                                               l.p.   673            0.5    (M--Ph.C.sub.6 H.sub.4                                                        CO.sub.2.sup.+=            1.  2-methylindan-2-yl                                                                              m.p. (M--CH.sub.3 --CH.sub.2).sup.+ =                                                        673.3598                                                                             (a)    588.2879                                              673.3616                (Calculated =                                                                 588.2876)                  2.  1-methylindan-2-yl                                                                              l.p.   702            0.4      R.sub.F = 0.8                                  m.p. M.sup.+   702.3989                                                                             (a)       (b)                                                702.3963                                                                 l.p.   687            0.2    (M--PhC.sub.6 H.sub.4                                                         CO.sub.2).sup.+=           3.  5-methylindan-2-yl                                                                              m.p. M.sup.+--CH.sub.3 =                                                                     687.3655                                                                             (c)    588.2862                                              687.3700                (Calculated =                                                                 588.2376)                                        l.p.   722            0.1    (M--PhC.sub.6 H.sub.4                                                         CO.sub.2).sup.+=           4.  5-chloroindan-2-yl                                                                              m.p. M.sup.+=  722.3442                                                                             (c)    608.2264                                              722.3369                (Calculated =                                                                 608.2329)                  5.  5,6-dichloroindan-2-yl                                                                          l.p.   756             0.15  (M--PhC.sub.6 H.sub.4                                                         CO.sub.2).sup.+=                                 m.p. M.sup.+=  756.3052                                                                             (d)    642.1949                                              756.2997                (Calculated =                                                                 642.1938)                  6.  1-indanyl         l.p.   687            0.5      R.sub.F = 0.5                                  m.p. M.sup.+--CH.sub.3                                                                       673.3598                                                                             (e)       (b)                                                = 573.3595                                         7.  2-indanylmethyl   mixed                                                                              M.sup.+ =        0.2    (M--PhC.sub.6 H.sub.4                                                         CO.sub.2).sup.+=                                      702.3943  702.3989                                                                             (d)    588.2903                                                                      (Calculated =                                                                 588.2876)                  8.  2-(2-indanyl)ether                                                                              l.p.   701            0.2    (M--PhC.sub.6 H.sub.4                                                         CO.sub.2).sup.+=                                 m.p. (M--CH.sub.3).sup.+=                                                                    701.3910                                                                             (d)    602.3006                                              701.3860                (Calculated =                                                                 602.3032)                  9.  1,2,3,4-tetrahydro-2-naphthyl                                                                   mixed                                                                              M.sup.+=         0.1      R.sub.F = 0.75                                      702.3970  702.3989                                                                             (f)       (b)                     10. 2,3-dihydro-5-methoxy-                                                                          l.p.   720                     R.sub.F = 0.5                benzo[b]fur-2-yl  m.p. M.sup.+=  720.3731                                                                             (k)       (g)                                                720.3717                                           11. 2,3-dihydro-6-methoxy-benzo-                                                                    l.p.   720                     R.sub.F = 0.6                [b]fur-2-yl       m.p. M.sup.+=  720.3731                                                                             (1)       (g)                                                720.3696                                           12. 5-chloro-2-methyl-chroman-                                                                      l.p.   752             0.12    R.sub.F = 0.69                                 m.p. M.sup.+=  752.3546                                                                             (f)       (g)                                                752.3542                                           13. 3-methylbenzo[1,4]oxazin-                                                                       l.p.   719            0.1      R.sub.F = 0.83               2-y1 m.p.         M.sup.+=                                                                           719.3890  (f)       (f)                                                       719.3895                                           14. benzo[b]fur-2-yl  mixed                                                                              M.sup.+=          0.45                                                        688.3480  688.3468                                                                             (h)       (i)                     15. benzo[b]thien-2-yl                                                                              mixed                                                                              M.sup.+=          0.44    R.sub.F = 0.86                                      704.3241  704.3240                                                                             (h)       (j)                     16. benzo[b]thien-3-yl                                                                              l.p.   704             0.32                                                   m.p. M.sup.+=  704.3240                                                                             (h)       (m)                                                704.3242                                           __________________________________________________________________________     *l.p. = less polar isomer                                                      m.p. = more polar isomer                                                

a. solvent system ; 10% methanol in methylene dichloride

b. solvent system ; 25% ethyl acetate in toluene

c. solvent system ; 10% ethyl acetate in methylene dichloride

d. solvent system ; 25% ethyl acetate in methylene dichloride

e. solvent system ; 10% methanol in ethyl acetate

f. solvent system ; 50% ethyl acetate in toluene

g. solvent system ; 20% ethyl acetate in toluene

h. solvent system ; ethyl acetate

i. In this example, the enone was prepared in the following manner:-

A solution of methyl7-[2β-formyl-3α,5α-di-(4-phenylbenzoyloxy)-cyclopent-1.alpha.-yl]hept-5-cis-enoate(200mg., 0.34 mmole) in dimethylformamide (2ml.) was added to a mixtureof dimethyl 2-(benzo[b]furan-2-yl)-2-oxoethylphosphonate (136mg., 0.5mmole) and sodium hydride (19mg., 0.45 mmole) in dimethylformamide(4ml.) at room temperature. After 1 hour the mixture was diluted withwater (10ml.) and extracted with ethyl acetate (3 × 5ml.). The combinedextracts were dried and the solvent was evaporated in vacuo to give thedesired enone, R_(F) = 0.35 (50% ethyl acetate in pentane).

j. solvent system; 10% methanol in toluene

k. characterised by its n.m.r. spectrum in deuteriochloroform (δvalues):-

3.35 & 3.72, 2H, double doublet, --CH₂ --P--,

3.58, 2h, doublet, dihydrofuryl C-3 protons,

3.81 & 4.00, 6H, double doublet, --P-(O--CH₃)₂,

3.90, 3h, singlet, aromatic methoxy protons,

5.29, 1H, triplet, dihydrofuryl C-2 proton,

6.87, 3H, singlet, aromatic protons.

1. Characterised by its n.m.r. spectrum in deuteriochloroform (δvalues):

3.20 & 3.59, 2H, double doublet, --CH₂ --P--,

3.36, 2h, doublet, dihydrofuryl C-3 protons,

3.68 & 3.87, 6H, double doublet, --P--(OCH₃)₂,

3.75, 3h, singlet, aromatic methoxy protons,

5.23, 1H, triplet, dihydrofuryl C-2 protons,

6.3-7.2, 3H, multiplet, aromatic protons.

m. In this example the enone was prepared in the following manner:-

A solution of methyl7-[2β-formyl-3α,5α-di(4-phenylbenzoyloxy)cyclopent-1.alpha.-yl]hept-5-cis-enoate(79mg., 0.12 mmole) and dimethyl2-(benzo[b]-thien-3-yl)-2-oxoethylphosphonate (71mg., 0.25 mmole) intoluene (2ml.) and t-butanol (1ml.) was treated with 1N sodium hydroxidesolution (212μl.) and stirred vigorously overnight. The mixture wasneutralised with hydrochloric acid, the organic phase was separated, andthe aqueous layer was extracted with methylene dichloride (3 × 5ml.).The combined organic extracts were dried, and the solvent was evaporatedin vacuo to give the desired enone, R_(F) = 0.66 (20% ethyl acetate intoluene).

2-Ethoxycarbonyl-4-methyl-1,4-benzoxazine, used as a starting materialfor the preparation of compound number 13, was prepared as follows:

Ethyl 1,4-benzoxazine-2-carboxylate (5.8g.) was disolved in acetonitrile(15ml.) under an atmosphere of argon. Formaldehyde (30ml. of a 37%aqueous solution) and lithium cyanoborohydride (4.67g.) were added, andthe solution was stirred for 5 minutes. Glacial acetic acid (3.5ml.) wasadded dropwise and over a period of 10 minutes, and the solution wasstirred at room temperature for 2 hours. More glacial acetic acid(3.5ml.) was added, and after 30 minutes the reaction mixture was pouredinto diethyl ether (200ml.), washed successively with 0.1N hydrochloricacid, sodium bicarbonate and brine, and was dried. The solvent wasevaporated to give the crude 2-carboxyethyl-4-methyl-1,4-benzoxazine,which was purified by chromatography on silica gel (148g.). Elution with10% ethyl acetate in toluene gave pure ethyl4-methyl-1,4-benzoxazine-2-carboxylate (5.9g.) whose n.m.r. spectrum indeuteriochloroform showed the following features (δ values):-

1.3, 3H, triplet (J = 7Hz), --CH₂ CH₃,

2.9, 3h, singlet, N-Me,

3.45, 2H, doublet (J = 4Hz), >N-CH₂ -CH<,

4.3, 2h, quartet, (J = 7Hz), --CH₂ --CH₃,

4.9, 1h, triplet, (J = 4Hz), --CH₂ CH<,

6.6-7.0, 4h, multiplet, aromatic protons,

Example 6

A solution of15-(5-chloro-2,3-dihydrobenzo[b]fur-2-yl)-9-oxo-11α,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid (68mg.) in tetrahydrofuran (0.5ml.) and a 2:1 mixture of aceticacid and water (4ml.) was stirred at 50°C. for 1 hour. The solvents werethen evaporated in vacuo and the residue was chromatographed on a columnof Mallinkrodt CC4 silica gel (4.4g.) using 30% acetone in cyclohexaneas eluant. Evaporation of the solvent gave the mixture of C-15 epimersof15-(5-chloro-2,3-dihydrobenzo[b]fur-2-yl)-11α,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, R_(F) = 0.3 and 0.4 respectively (3% aceticacid in ethyl acetate). The n.m.r. spectrum in deuterated acetone showedthe following characteristic features (δ values):

3.17, 2H, doublet, dihydrofuryl C-3 proton,

3.9-4.4, 2H, multiplet, 2 --CH(OH)--,

4.78, 1h, multiplet, dihydrofuryl C-2 proton,

5.34, 2H, multiplet, cis-olefinic protons,

5.78, 2H, multiplet, trans-olefinic protons,

6.6-7.2, 3H, multiplet, aromatic protons.

The mass spectrum showed M⁺⁼ 679.2902 (calculated for C₃₃ H₅₄ ClNO₆ Si₃= 679.2947).

The starting material for the above process was obtained as follows:

A solution of15-(5-chloro-2,3-dihydrobenzo[b]-fur-2-yl)-9α-hydroxy-11α,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid (96mg. 0.16 mmole) in acetone (2ml.) at 0°C., was treated with 8Nchromic acid (51.7μl., 0.41 mmole) for 45 minutes. Isopropanol wasadded, and the solution was diluted with ethyl acetate (15ml.), washedwith brine (10ml.) and dried. Evaporation of the solvent gave the mixedC-15 epimers of15-(5-chloro-2,3-dihydrobenzo[b]fur-2-yl)-9-oxo-11α,15-bis(tetrahydropyran-2-yloxy)-16,17,18,29,20-pentanor-5-cis,13-trans-prostadienoicacid, R_(F) = 0.4 (5% methanol in methylene dichloride).

This bis(tetrahydropyranyl) ether used in the preparation was obtainedby the process described in the second part of Example 1, using methyl5-chloro-2,3-dihydrobenzo[b]furan-2-carboxylate in place of methyl2,3-dihydrobenzo[b]furan-2-carboxylate.

Example 7

The process described in Example 6 was repeated, using the appropriatebis(tetrahydropyranyl) ether obtained as described in Example 1, to givethe 9-oxo compounds shown in the table below. The products wereidentified by n.m.r. spectroscopy and are characterised by accurate massmeasurement by mass spectrometry of the molecular ion of themethoxime-tris(trimethylsilyl)derivative, or in the case of compound 4the methoxime-bis(trimethylsilyl ether)-methyl ester derivative.##SPC14##

                       Mass spectrum                                              No.     R           Isomer*  Found   Calculated                               ______________________________________                                        1.   2,3-dihydrobenzo[b]-                                                                         mixed    M.sup.+=                                                                              645.3337                                      fur-2-yl                645.3338                                         2.   benzo[1,3]dioxol-       M.sup.+=                                              2-yl           mixed    647.3129                                                                              647.3129                                 3.   1-benzocyclobutanyl                                                                          mixed    M.sup.+=                                                                      629.3376                                                                              629.3388                                 4.   2-indanyl      l.p.      585                                                                 m.p.     M.sup.+=                                                                              585.3306                                                              585.3303                                         ______________________________________                                         *l.p. = less-polar isomer                                                      m.p. = more-polar isomer                                                

Example 8

The process described in the first part of example 2 was repeated usingmethyl15-(5-chloroindan-2-yl)-11α,15-dihydroxy-2-methyl-9α-(4-phenylbenzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate as the startingmaterial, to give15-(5-chloroindan-2-yl)-9α,11α,15-trihydroxy-2-methyl-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, which was separated into more polarand less polar epimers on preparative thin layer chromatography, R_(F) =0.15 and 0.30 respectively (3% acetic acid in ethyl acetate). The massspectrum of the more polar isomer had M⁺ = 736.3598 (calculated for C₃₇H₆₅ C/O.sub. 5 Si₄ = 736.3562).

The starting material was prepared by the process described in thesecond part of Example 2 using(4-carboxy-3-methylbutyl)triphenylphosphonium bromide in place of(4-carboxybutyl)triphenylphosphonium bromide, via the followingintermediates:

7-[2β-dimethoxymethyl-5α-hydroxy-3α-(tetrahydropyran-2-yloxy)cyclopent-1α-yl]-2-methyl-5-cis-heptenoicacid, R_(F) = 0.26 (5% methanol in methylene chloride), n.m.r. indueterated chloroform:

δ1.1-1.2, 3H, doublet, CH₃ --CH< ,

3.35, 6h, singlet, --CH(OCH₃)₂.

Methyl 7-[2β-dimethoxymethyl-5α-hydroxy-3α-tetrahydropyran-2-yloxy)cyclopent-1α-yl]-2-methyl-5-cis-heptenoate,R_(F) = 0.33 (5% methanol in methylene chloride), n.m.r. in deuteratedchloroform:

δ1.1-1.2, 3H, doublet, CH₃.CH<,

3.35, 6h, singlet, --CH(OCH₃)₂,

3.65, 3h, singlet, --COOCH₃ .

Methyl7-[2β-dimethoxymethyl-5α-(4-phenylbenzoyloxy)-3α-(tetrahydropyran-2-yloxy)cyclopent-1α-yl]-2-methyl-5-cis-heptenoate,R_(F) = 0.55 (ether), n.m.r. in deuterated chloroform:

δ0.9-1.1, 3H, CH₃ -CH< ,

3.4, 6h, --ch(och₃)₂,

3.6, 3h, --cooch₃,

7.2-8.3, 9h, aromatic protons.

Methyl7-[2β-dimethoxymethyl-3α-hydroxy-5α-(4-phenylbenzoyloxy)cyclopent-1α-yl]-2-methyl-5-cis-heptenoate,R_(F) 32 0.42 (ether), n.m.r. in deuterated chloroform:

δ0.9-1.2, 3H, CH₃ CH<,

3.4, 6h, --ch(och₃)₂,

3.6, 3h, --cooch₃.

methyl 7-[2β-formyl-3α-hydroxy-5α-(4-phenylbenzoyloxy)-cyclopent-1α-yl]-2-methyl-5-cis-heptenoate, R_(F)= 0.48 (ether).

Methyl15-(5-chloroindan-2-yl)-11α-hydroxy-2-methyl-15-oxo-9α-(4-phenylbenzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate,R_(F) = 0.4 (20% ethyl acetate in methylene dichloride), n.m.r. indeuterated chloroform (δ values):

1.0, 3H, doublet CH₃ --CH<,

3.15--3.22, 4h, multiplet, indane C1 & C3 protons,

3.58, 3H, singlet, --CO₂ CH₃.

Methyl 15-(5-chloroindan-2-yl)-11α,15-dihydroxy-2-methyl-9α-(4-phenylbenzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate, R_(F) = 0.1 (20% ethyl acetate in methylenechloride).

Example 9

The process described in the first part of Example 8 was repeated usingmethyl15-(5-chloro-2,3-dihydrobenzo[b]fur-2-yl)-11α,15-dihydroxy-2-methyl-9α-(4-phenylbenzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-transprostadienoateas the starting material, to give the separated C-15 epimers of15-(5-chloro-2,3-dihydro-benzo[b]-fur-2-yl)-9α,11α,15-trihydroxy-2-methyl-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic cid, R_(F) = 0.45 and 0.50 respectively (3%acetic acid in ethyl acetate). The n.m.r. spectrum of each epimer indeuterated acetone showed the following characteristic features (δvalues):

1.15 3H, doublet, >CH-CH₃,

3.21, 2h, doublet, dihydrofuryl C-3 protons,

3.8-4.4, 3H, multiplet, 3 --CH(OH)--,

4.82, 1h, multiplet, dihydrofuryl C-2 proton,

5.2-5.8, 4H, multiplet, olefinic protons,

6.6-6.7, 3H, multiplet, aromatic protons.

The mass spectrum of the more polar epimer had M⁺ = 738.3392 (calculatedfor C₃₆ H₆₃ ClO.sub. 6 Si₄ = 738.3391)

The starting material used in the above preparation was prepared frommethyl7-[2β-formyl-3α-hydroxy-5α-(4-phenylbenzoyloxy)cyclopent-1α-yl]-2-methyl-5-cis-heptenoateby the process described in the latter part of Example 8, via thefollowing intermediates:

Methyl 15-(5-chloro-2,3-dihydrobenzo[b]fur-2-yl)-11α-hydroxy-2-methyl-15-oxo-9α-(4-phenylbenzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate,R_(F) = 0.8 (50% ethyl acetate in toluene).

Methyl15-(5-chloro-2,3-dihydrobenzo[b]fur-2-yl)-11α,15-dihydroxy-2-methyl-9α-(4-phenylbenzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate,R_(F) = 0.1 and 0.2 (ether).

Example 10

To a solution of a mixture of C-15 epimers of methyl15-(5-chloroindan-2-yl)-15-hydroxy-9α,11α-bis(4-phenylbenzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-transprostadienoate(183mg., 0.227 mmole) in methanol (12ml.) containing1,2-dimethoxymethane (4ml.) was added anhydrous potassium carbonate(125mg.), and the mixture was stirred at room temperature for 18 hours.The solution was adjusted to pH 7 with 1N hydrochloric acid and thesolvent was evaporated in vacuo. The residue was treated with water(10ml.) and extracted with ethyl acetate (2 × 50ml.). The combinedextracts were dried, the solvent was evaporated in vacuo, and theresidue was chromatographed on preparative thin layer plates, developedin ethyl acetate, to give the separated C-15 epimers of methyl15-(5-chloroindan-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate,R_(F) = 0.2 and 0.3 respectively (ethyl acetate). The mass spectrum hadM⁺ = 664.3207 (calculated for C₃₄ H₅₇ ClO.sub. 5 Si₃ = 664.3202).

Example 11

The process described in Example 10 was repeated using methyl15-(2,3-dihydrobenzo[b]thien-2-yl)-15-hydroxy-9α,11α-bis(4-phenylbenzoyloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate as the starting material, to give theseparated C-15 epimers of methyl15-(2,3-dihydro-benzo[b]thien-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor5-cis,13-trans-prostadienoate,R_(F) = 0.30 and 0.40 respectively (ethyl acetate). The mass spectrumhad M⁺ = 646.2982 (calculated for C₃₃ H₅₆ O₅ SSi₃ = 646.3000).

The intermediate enone used in the process was obtained by the methodgiven in note (m) of Example 5.

Example 12

A solution of9α,11α,15-trihydroxy-15-(2,3-dihydrobenzo[b]fur-2-vl)-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid (5mg.) was dissolved inmethanol (0.1ml.) and excess diazomethane was added aat 0°C. Thesolvents were removed in vacuo to give a mixture of C-15 epimers ofmethyl9α,11α,15-trihydroxy-15-(2,3-dihydrobenzo[b]fur-2-yl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate, R_(F) = 0.3 (ethyl acetate). The mass spectrumhad M⁺ = 632.3344 (calculated for C₃₃ H₅₆ O₆ Si₃ = 632.3385).

Example 13

To a solution of the more polar epimers of methyl15-(5-chloroindan-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate(14mg.) in tetrahydrofuran (1ml.) and ether (3ml.) was added lithiumaluminium hydride (24mg.). The mixture was stirred at room temperaturefor 1 hour, the excess of hydride was destroyed by the addition of water(1ml.), and the mixture was extracted with ethyl acetate to give15-(5-chloroindan-2-yl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadien-1,9α,11α,15-tetraol.M⁺ = 708.3618 (calculated for C₃₆ H.sub. 65 Cl0₄ Si₄ = 708.3648), R_(F)= 0.2 (5% methanol in ethyl acetate).

Example 14

                            % w/v                                                 ______________________________________                                        15-(5-chlorindan-2-yl)-9α,11α,15-                                 trihydroxy-16,17,18,19,20-pentanor-                                           5-cis,13-trans-prostadienoic acid                                                                       0.003                                               Sodium phosphate B.P.     2.90                                                Sodium acid phosphate B.P.                                                                              0.30                                                Water for injection       to 100                                              ______________________________________                                    

The sodium phosphate B.P. was dissolved in about 80% of the water,followed by the prostadienoic acid derivative, and when dissolved, thesodium phosphate B.P. The solution was made up to volume with water forinjection, and the pH was checked to be between 6.7 and 7.7. Thesolution was filtered to remove particulate matter, sterilised byfiltration, and filled into pre-sterilised neutral glass ampoules underaseptic conditions. Immediately before use, the contents of an ampouleare diluted in sodium chloride B.P. for administration by intravenousinfusion.

The prostadienoic acid derivative may, of course, be replaced by anequivalent amount of another prostanoic acid derivative of theinvention.

Example 15

The process described in Example 14 was repeated, omitting the sodiumphophate B.P. and sodium acid phosphate B.P., to give ampoulescontaining a sterile aqueous solution of15-(5-chloroindan-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid, which are used in the manner described in Example 14.

The prostadienoic acid derivative may be replaced by an equivalentamount of another prostadienoic acid of the invention, to give othersterile aqueous solutions.

What we claim is:
 1. A cyclopentane derivative of the formula:##SPC15##wherein R¹ is carboxy or alkoxycarbonyl of up to 11 carbonatoms, R² is hydroxy or alkanoyloxy of 1 to 4 carbon atoms, and R³ ishydrogen, or R² and R³ together are oxo, X is ethylene or cis-vinylene,Y is ethylene or trans-vinylene, Z is a direct bond or alkylidene of 1to 5 carbon atoms, either A and B are each is alkylidene of 1 to 5carbon atoms or A is ethylene, and B is a direct bond, R⁴ is hydrogen oralkyl of 1 to 4 carbon atoms, or Cr⁴ together with an adjacent carbon ofA or B forms a double bond, R⁵ is halogen or alkyl, alkoxy orhalogenoalkyl each of 1 to 5 carbon atoms,which compound bears 0 or 1alkyl substituent of 1 to 4 carbon atoms on the trimethylene group, andfor those compounds wherein R¹ is carboxy, the pharmaceutically orveterinarily acceptable base addition salts thereof.
 2. The cyclopentanederivative f claim 1 wherein ##SPC16##is 1-indanyl, 2-indanyl,2-indanylmethyl or 2-(2-indanyl)ethyl, wherein R⁵ and n are as definedin claim
 1. 3. The cyclopentane derivative of claim 2 whereinR¹ iscarboxy or methoxycarbonyl, R² is hydroxy, R³ is hydrogen, or R² and R³together are oxo, X is cis-vinylene, Y is trans-vinylene, and ##SPC17##A1-indanyl, 2-indanyl, 1-methyl-2-indanyl, 2-methyl-2-indanyl,5-methyl-2-indanyl, 5-chloro-2-indanyl, 5,6-dichloro-2-indanyl,5-chloro-2-methyl-2-indanyl, 2-indanylmethyl or 2-(2-indanyl)ethylbenzo[1,3]-which compound bears 0 or 1 methyl substituent on carbon atom2.
 4. The cyclopentane derivative of claim 1 which has the formula:-##SPC18##wherein R.sup. 1 is carboxy or methoxycarbonyl, R² is hydroxyand R³ is hydrogen or R² and R³ together are oxo, R⁴ is hydrogen ormethyl, A and B are both methylene and R⁵ is hydrogen, chlorine, bromineor methyl, and for those compounds wherein R¹ is carboxy, thepharmaceutically or veterinarily acceptable base addition salts thereof.5. The cyclopentane derivative of claim 1 which is15-(5-chloroindan-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid.
 6. The cyclopentane derivative of claim 1 which is methyl15-(5-chloroindan-2-yl)-9α,11α,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate,9α,11α,15-trihydroxy-15-(2-methylindan-2-yl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid,9α,11α,15-trihydroxy-15-(5-methylindan-2-yl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid or9α,11α,15-trihydroxy-15-(2-indanyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoicacid.